Growth hormone (GH)-releasing hormone (GHRH) is a hypothalamic neurocrine which stimulates pituitary GH secretion. GHRH has become one of the best documented sleep promoting substances; much of this evidence was generated under the auspices of the previous grant. The aims of the present proposal are to study the possible humoral mechanisms involved in the sleep promoting activity of GHRH, and the contribution of GHRH to enhanced sleep elicited by heat exposure, interleukin-1 (IL1) (the key cytokine responsible for the acute phase response to infections), and by sleep deprivation. l) The role of GH in sleep has been controversial ever since a sleep-associated secretion of GH was first reported more than 20 years ago. The discovery of the sleep promoting activity of GHRH reopened this discussion. The effects on sleep of exogenous species specific GH and immunoneutralization of endogenous GH will be studied. The sleep promoting activity of GHRH will be tested in hypophysectomized rats and in rats pretreated with antiserum to GH. Many GH effects are mediated by insulin-like growth factor-I (IGF-I). Alterations in sleep in response to exogenous IGF-I will be studied in comparison with the sleep effects of the structurally homologous IGF-II and insulin. These experiments will help clarify the role of GH and IGF-I in sleep regulation and in the sleep enhancing actions of GHRH. 2) Models of sleep regulation distinguish between stimuli facilitating sleep by lowering the "sleep threshold" and stimuli acting on the "homeostatic mechanisms of sleep regulation". Heat and IL1 are putative inputs for "homeostatic sleep mechanisms", and they are also known to release GHRH. The involvement of GHRH in the sleep response to heat and IL1 will be studied in rats after immunoneutralization of GHRH. These experiments may contribute to an identification of the theoretically postulated "homeostatic sleep mechanisms". 3) Sleep pressure increases as the function of wakefulness and discharges in an enhanced recovery sleep after sleep loss. Previous studies indicate that both GHRH and IL1 are involved in the mechanisms of recovery sleep. To determine whether GHRH is one of the substances responsible for the increased sleep pressure elicited by sleep loss, hypothalamic GHRH concentration will be measured during and after sleep deprivation in normal rats and in rats pretreated with antibodies to IL1. The latter experiments will decide whether IL1 is an input for GHRH. All the proposed experiments will be carried out on rats except that the effects of IGF-I on sleep will also be tested in rabbits.